Effect of pepsin on maintaining the supersaturation of the HCl salt of a weakly basic drug: a case study

The impact of pepsin on the maintenance of supersaturated solution of the HCl salt of a weakly basic drug was evaluated in simulated gastric fluid by monitoring the drug solubility in the absence and presence of pepsin. In the presence of pepsin, the HCl salt maintained its apparent solubility through 24?h, whereas, no such solubility advantage was seen in the absence of pepsin. Consequently, a minimum inhibitory concentration of pepsin is required for maintenance of supersaturation. In addition, NMR study seems to indicate a molecular level interaction between pepsin and HCl salt leading to a weak binding between the two. Therefore, for the HCl salts of weak bases having disproportionation potential, it is preferred that preformulation solubility studies are conducted in the presence of pepsin to reflect their in vivo behavior in maintaining supersaturation solubility.     

The influence of levodopa-induced dyskinesias on manual tracking in patients with Parkinson’s disease

The influence of peak-dose, levodopa-induced dyskinesias (LID) on manual tracking (MT) was examined in 10 dyskinetic patients with Parkinson’s disease (DPD), and compared to 10 age/gender-matched non-dyskinetic patients with Parkinson’s disease (NDPD) and 10 healthy controls. Whole-body movement (WBM) and MT performance were recorded simultaneously with a 6-degrees-of-freedom magnetic motion tracker and forearm rotation sensors, respectively. Subjects were asked to match the length of a computer-generated line with a line they controlled via wrist rotation. Results show that DPD patients had greater WBM magnitude at rest and during the motor task, both in displacement and in velocity. All groups displayed some increase in WBM displacement from rest to MT, but only the DPD group had a significant increase in WBM velocity during movement. As for MT performance (determined by assessing the positional mismatch between subjects’ and target lines), ERROR in displacement was statistically similar between groups. There was no correlation between ERROR and the magnitude of WBM within the DPD group. The DPD group showed significant increased ERROR when the velocity of the subject’s line was compared with that of the velocity of the target line. When two distinct target pace segments were examined (FAST/SLOW), no significant differences were found in ERROR for displacement for either group, but both the NDPD and DPD group showed increased ERROR from SLOW to FAST for velocity. This was accompanied with an increase in WBM velocity only in the DPD group. The lack of increased ERROR during the SLOW tracking portion in the DPD group supports the notion that the dyskinesias themselves were not primarily responsible for the ERROR seen in the patients. When examining the positive or negative values of ERROR (i.e., faster or slower than the target), we found that the increased ERROR in velocity observed in the DPD group was the result of excess velocity rather than bradykinesia, manifested as isolated deviations from the target trace in the DPD group that were coherent in time with increased ERROR in velocity. In conclusion, evidence presented in the present study shows that the LID was not the primary cause of the ERROR seen in the DPD group. Accordingly, we propose that the increased ERROR seen in the DPD group resulted from a mechanism distinct from the one generating LID.     

Translating research into action: WHO evidence-informed guidelines for safe and effective micronutrient interventions

In 2009 WHO adopted a new process by which recommendations for safe and effective micronutrient interventions are developed, ensuring the use of best practices and available evidence. This process includes nine steps ranging from establishing steering and guideline groups and prioritizing needs to planning the implementation and updating the guidelines. Systematic reviews of evidence are used to address critical outcomes for decision making, considering the balance among risks and benefits, values, preferences, and costs. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess the overall evidence quality and establish the strength of the recommendations. Guideline development is underway for interventions covering iron and vitamin A supplementation, home fortification with multiple micronutrient powders, and fortification of staple foods. Global guidelines are disseminated through the WHO electronic Library of Evidence for Nutrition Actions, a resource of the evidence and tools for scaling-up micronutrient interventions. The WHO Department of Nutrition for Health and Development and the Evidence-Informed Policy Network will support countries to scale-up the delivery of micronutrient interventions by adapting these evidence-informed guidelines and policies to make them context specific. This will be accomplished by providing summaries of the best available evidence on micronutrient interventions, evidence on health systems, and effective delivery systems along with capturing the tacit knowledge of the countries' realities. With a systematic approach that uses the WHO strategy on research for health as the connecting thread, the challenges to successfully implement safe and effective micronutrient programs can be addressed.     

Peripheral trauma induced dystonia or post-traumatic syndrome?

The relationship between peripheral trauma and dystonia has been debated for more than a century but the issue still remains controversial. There are passionate supporters and detractors of the association and both the groups have their own arguments. This review aims to critically evaluate those arguments and presents current understanding of this association. In the process, the relevant case series and scientific papers exploring this subject have been discussed. Upon careful review of available literature coupled with their own experience, the authors believe that peripheral trauma can predispose to abnormal posturing of a body part after variable intervals. To call this posturing a "post-traumatic dystonia" might be premature and the term "post-traumatic syndrome" can be used instead. More work is needed to unravel the pathophysiology of this post-traumatic syndrome.     

Levodopa and Parkinson disease--electrophysiological perspectives in animal models

Chronic administration of levodopa, while producing an “awakening” in patients with Parkinson disease (PD), causes disabling side effects such as motor fluctuations and dyskinesia. Indeed the most common reason for deep brain stimulation (DBS) in patients with PD is for treating these complications. However, our understanding of the complexities of these complications is still in the early days. Animal models (primate and rodent) have been exceedingly helpful in elucidating some of the mechanisms. More work needs to be done. In the paper by Gilmour et al. (2011) the authors have investigated the neuronal firing properties and local field potentials of two basal ganglia structures, in response to chronic treatment, to tackle this very question. This commentary attempts to place the work in the context of PD animal models, electrophysiology and where we need to go.     

Clinical outcome of shoulder muscle transfer for shoulder deformities in obstetric brachial plexus palsy: A study of 150 cases

Background:

Residual muscle weakness, cross-innervation (caused by misdirected regenerating axons), and muscular imbalance are the main causes of internal rotation contractures leading to limitation of shoulder joint movement, glenoid dysplasia, and deformity in obstetric brachial plexus palsy. Muscle transfers and release of antagonistic muscles improve range of motion as well as halt or reverse the deterioration in the bony architecture of the shoulder joint. The aim of our study was to evaluate the clinical outcome of shoulder muscle transfer for shoulder abnormalities in obstetric brachial plexus palsy.

Materials and Methods:

One hundred and fifty patients of obstetric brachial plexus palsy with shoulder deformity underwent shoulder muscle transfer along with anterior shoulder release at our institutions from 1999 to 2007. Shoulder function was assessed both preoperatively and postoperatively using aggregate modified Mallet score and active and passive range of motion. The mean duration of follow-up was 4 years (2.5–8 years).

Results:

The mean preoperative abduction was 45° ± 7.12, mean passive external rotation was 10° ± 6.79, the mean active external rotation was 0°, and the mean aggregate modified Mallet score was 11.2 ± 1.41. At a mean follow-up of 4 years (2.5–8 years), the mean active abduction was 120° ± 18.01, the mean passive external rotation was 80° ± 10.26, while the mean active external rotation was 45° ± 3.84. The mean aggregate modified Mallet score was 19.2 ± 1.66.

Conclusions:

This procedure can thus be seen as a very effective tool to treat internal rotation and adduction contractures, achieve functional active abduction and external rotation, as well as possibly prevent glenohumeral dysplasia, though the long-term effects of this procedure may still have to be studied in detail clinico-radiologically to confirm this hypothesis.

Level of evidence:

Therapeutic level IV     

Understanding drug-excipient compatibility: Oxidation of compound A in a solid dosage form

Drug-excipient compatibility studies lay the foundation for designing a chemically stable formulation for clinical and commercial development. This article describes the investigation of oxidative degradation encountered with compound A (a phenylalanine-drug complex) in a capsule dosage form. Two wet- granulation capsule formulations (2.5-mg and 25-mg strengths) were developed using excipients that showed satisfactory stability from initial drug-excipient compatibility studies. Both capsule strengths were chemically stable at 50°C (closed) for at least 18 weeks, but they showed discoloration. The 2.5-mg capsule exhibited degradation after four weeks at 40°C/75%RH (open) besides discoloration. LC/MS analysis indicated that the degradants were oxidation products of the parent compound. Oxidation of compound A was investigated by forced degradation with peroxide, use of isotopically labeled water (H₂¹⁸O) to study the source of oxygen, and use of different antioxidants to mitigate oxidation. Excipient(s) responsible for oxidation and discoloration were identified through extended and modified excipient compatibility studies. The discoloration was indicative of Maillard reaction occurring between a reducing sugar impurity from microcrystalline cellulose and L-phenylalanine in the drug complex. Reactive oxidative species generated by this reaction is postulated to cause oxidation of compound A.